Epigenetic Mechanisms of Mental Retardation

  • Anne Schaefer
  • Alexander Tarakhovsky
  • Paul Greengard
Part of the Progress in Drug Research book series (PDR, volume 67)


Mental retardation is a common form of cognitive impairment affecting ~3% of the population in industrialized countries. The mental retardation syndrome incorporates a highly diverse group of mental disorders characterized by the combination of cognitive impairment and defective adaptive behavior. The genetic basis of the disease is strongly supported by identification of the genetic lesions associated with impaired cognition, learning, and social adaptation in many mental retardation syndromes. Several of the impaired genes encode epigenetic regulators of gene expression. These regulators exert their function through genome-wide posttranslational modification of histones or by mediating and/or recognizing DNA methylation. In this chapter, we review the most recent advances in the field of epigenetic mechanisms of mental retardation. In particular, we focus on animal models of the human diseases and the mechanism of transcriptional deregulation associated with changes in the cell epigenome.


Mental Retardation Histone Acetylation Nonneuronal Cell Histone Lysine Methylation Mental Retardation Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to especially thank Eric Nestler for critical reading of the review and Debra Poulter for her help in the preparation of the chapter. We would like to recognize and apologize to colleagues whose work could not be acknowledged due to space limitations.


  1. 1.
    Jackson A, Moritz CT, Mavoori J, Lucas TH, Fetz EE (2006) The Neurochip BCI: towards a neural prosthesis for upper limb function. IEEE Trans Neural Syst Rehabil Eng 14:187–190PubMedCrossRefGoogle Scholar
  2. 2.
    Hochberg LR, Serruya MD, Friehs GM, Mukand JA, Saleh M, Caplan AH, Branner A, Chen D, Penn RD, Donoghue JP (2006) Neuronal ensemble control of prosthetic devices by a human with tetraplegia. Nature 442:164–171PubMedCrossRefGoogle Scholar
  3. 3.
    Velliste M, Perel S, Spalding MC, Whitford AS, Schwartz AB (2008) Cortical control of a prosthetic arm for self-feeding. Nature 453:1098–1101PubMedCrossRefGoogle Scholar
  4. 4.
    Moritz CT, Perlmutter SI, Fetz EE (2008) Direct control of paralysed muscles by cortical neurons. Nature 456:639–642PubMedCrossRefGoogle Scholar
  5. 5.
    Qiu Z, Ghosh A (2008) A brief history of neuronal gene expression: regulatory mechanisms and cellular consequences. Neuron 60:449–455PubMedCrossRefGoogle Scholar
  6. 6.
    Ooi L, Wood IC (2008) Regulation of gene expression in the nervous system. Biochem J 414:327–341PubMedCrossRefGoogle Scholar
  7. 7.
    Greenberg ME, Greene LA, Ziff EB (1985) Nerve growth factor and epidermal growth factor induce rapid transient changes in proto-oncogene transcription in PC12 cells. J Biol Chem 260:14101–14110PubMedGoogle Scholar
  8. 8.
    Greenberg ME, Ziff EB, Greene LA (1986) Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234:80–83PubMedCrossRefGoogle Scholar
  9. 9.
    Ginty DD, Bading H, Greenberg ME (1992) Trans-synaptic regulation of gene expression. Curr Opin Neurobiol 2:312–316PubMedCrossRefGoogle Scholar
  10. 10.
    Guitart X, Thompson MA, Mirante CK, Greenberg ME, Nestler EJ (1992) Regulation of cyclic AMP response element-binding protein (CREB) phosphorylation by acute and chronic morphine in the rat locus coeruleus. J Neurochem 58:1168–1171PubMedCrossRefGoogle Scholar
  11. 11.
    Montminy MR, Low MJ, Tapia-Arancibia L, Reichlin S, Mandel G, Goodman RH (1986) Cyclic AMP regulates somatostatin mRNA accumulation in primary diencephalic cultures and in transfected fibroblast cells. J Neurosci 6:1171–1176PubMedGoogle Scholar
  12. 12.
    Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH (1986) Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci USA 83:6682–6686PubMedCrossRefGoogle Scholar
  13. 13.
    Montminy MR, Bilezikjian LM (1987) Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 328:175–178PubMedCrossRefGoogle Scholar
  14. 14.
    Morgan JI, Cohen DR, Hempstead JL, Curran T (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237:192–197PubMedCrossRefGoogle Scholar
  15. 15.
    Sheng M, Thompson MA, Greenberg ME (1991) CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252:1427–1430PubMedCrossRefGoogle Scholar
  16. 16.
    Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038PubMedCrossRefGoogle Scholar
  17. 17.
    Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P (2008) Decoding the epigenetic language of neuronal plasticity. Neuron 60:961–974PubMedCrossRefGoogle Scholar
  18. 18.
    Cheung P, Allis CD, Sassone-Corsi P (2000) Signaling to chromatin through histone modifications. Cell 103:263–271PubMedCrossRefGoogle Scholar
  19. 19.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMedCrossRefGoogle Scholar
  20. 20.
    Crosio C, Heitz E, Allis CD, Borrelli E, Sassone-Corsi P (2003) Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons. J Cell Sci 116:4905–4914PubMedCrossRefGoogle Scholar
  21. 21.
    Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412PubMedCrossRefGoogle Scholar
  22. 22.
    Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedCrossRefGoogle Scholar
  23. 23.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedCrossRefGoogle Scholar
  24. 24.
    Daniel JA, Pray-Grant MG, Grant PA (2005) Effector proteins for methylated histones: an expanding family. Cell Cycle 4:919–926PubMedCrossRefGoogle Scholar
  25. 25.
    Brenner C, Fuks F (2007) A methylation rendezvous: reader meets writers. Dev Cell 12:843–844PubMedCrossRefGoogle Scholar
  26. 26.
    Ruthenburg AJ, Li H, Patel DJ, Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8:983–994PubMedCrossRefGoogle Scholar
  27. 27.
    Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97PubMedCrossRefGoogle Scholar
  28. 28.
    Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436:1103–1106PubMedCrossRefGoogle Scholar
  29. 29.
    Klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8:307–318PubMedCrossRefGoogle Scholar
  30. 30.
    Shi Y (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8:829–833PubMedCrossRefGoogle Scholar
  31. 31.
    Shi Y, Whetstine JR (2007) Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25:1–14PubMedCrossRefGoogle Scholar
  32. 32.
    Cloos PA, Christensen J, Agger K, Helin K (2008) Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev 22:1115–1140PubMedCrossRefGoogle Scholar
  33. 33.
    Agger K, Christensen J, Cloos PA, Helin K (2008) The emerging functions of histone demethylases. Curr Opin Genet Dev 18:159–168PubMedCrossRefGoogle Scholar
  34. 34.
    Pasini D, Bracken AP, Agger K, Christensen J, Hansen K, Cloos PA, Helin K (2008) Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harb Symp Quant Biol 73:253–263PubMedCrossRefGoogle Scholar
  35. 35.
    Lan F, Nottke AC, Shi Y (2008) Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol 20:316–325PubMedCrossRefGoogle Scholar
  36. 36.
    Inlow JK, Restifo LL (2004) Molecular and comparative genetics of mental retardation. Genetics 166:835–881PubMedCrossRefGoogle Scholar
  37. 37.
    Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T (2006) Genetics and pathophysiology of mental retardation. Eur J Hum Genet 14:701–713PubMedCrossRefGoogle Scholar
  38. 38.
    Froyen G, Bauters M, Voet T, Marynen P (2006) X-linked mental retardation and epigenetics. J Cell Mol Med 10:808–825PubMedCrossRefGoogle Scholar
  39. 39.
    Maekawa M, Watanabe Y (2007) Epigenetics: relations to disease and laboratory findings. Curr Med Chem 14:2642–2653PubMedCrossRefGoogle Scholar
  40. 40.
    Baker LA, Allis CD, Wang GG (2008) PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat Res 647:3–12PubMedCrossRefGoogle Scholar
  41. 41.
    Grant ME (2008) The epigenetic origins of mental retardation. Clin Genet 73:528–530PubMedCrossRefGoogle Scholar
  42. 42.
    Akbarian S, Huang HS (2009) Epigenetic regulation in human brain-focus on histone lysine methylation. Biol Psychiatry 65:198–203PubMedCrossRefGoogle Scholar
  43. 43.
    Kramer JM, van Bokhoven H (2009) Genetic and epigenetic defects in mental retardation. Int J Biochem Cell Biol 41:96–107PubMedCrossRefGoogle Scholar
  44. 44.
    Graff J, Mansuy IM (2009) Epigenetic dysregulation in cognitive disorders. Eur J Neurosci 30:1–8PubMedCrossRefGoogle Scholar
  45. 45.
    Levenson JM, Sweatt JD (2005) Epigenetic mechanisms in memory formation. Nat Rev Neurosci 6:108–118PubMedCrossRefGoogle Scholar
  46. 46.
    Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367PubMedCrossRefGoogle Scholar
  47. 47.
    Renthal W, Nestler EJ (2008) Epigenetic mechanisms in drug addiction. Trends Mol Med 14:341–350PubMedCrossRefGoogle Scholar
  48. 48.
    Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, Yasui DH, Kumar A, Nestler EJ, Akbarian S, Beckel-Mitchener AC (2008) Epigenetics in the nervous system. J Neurosci 28:11753–11759PubMedCrossRefGoogle Scholar
  49. 49.
    Costa E, Chen Y, Dong E, Grayson DR, Kundakovic M, Maloku E, Ruzicka W, Satta R, Veldic M, Zhubi A et al (2009) GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability. Expert Rev Neurother 9:87–98PubMedCrossRefGoogle Scholar
  50. 50.
    Akbarian S (2009) The molecular pathology of schizophrenia-Focus on histone and DNA modifications. Brain Res Bull [Epub ahead of print]Google Scholar
  51. 51.
    Urdinguio RG, Sanchez-Mut JV, Esteller M (2009) Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 8:1056–1072PubMedCrossRefGoogle Scholar
  52. 52.
    Oda H, Okamoto I, Murphy N, Chu J, Price SM, Shen MM, Torres-Padilla ME, Heard E, Reinberg D (2009) Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol Cell Biol 29:2278–2295PubMedCrossRefGoogle Scholar
  53. 53.
    Cao R, Zhang Y (2004) The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev 14:155–164PubMedCrossRefGoogle Scholar
  54. 54.
    Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849PubMedCrossRefGoogle Scholar
  55. 55.
    Shilatifard A (2006) Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75:243–269PubMedCrossRefGoogle Scholar
  56. 56.
    Ruthenburg AJ, Allis CD, Wysocka J (2007) Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25:15–30PubMedCrossRefGoogle Scholar
  57. 57.
    Li J, Moazed D, Gygi SP (2002) Association of the histone methyltransferase Set2 with RNA polymerase II plays a role in transcription elongation. J Biol Chem 277:49383–49388PubMedCrossRefGoogle Scholar
  58. 58.
    Krogan NJ, Kim M, Tong A, Golshani A, Cagney G, Canadien V, Richards DP, Beattie BK, Emili A, Boone C et al (2003) Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol Cell Biol 23:4207–4218PubMedCrossRefGoogle Scholar
  59. 59.
    Xiao T, Hall H, Kizer KO, Shibata Y, Hall MC, Borchers CH, Strahl BD (2003) Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev 17:654–663PubMedCrossRefGoogle Scholar
  60. 60.
    Kizer KO, Phatnani HP, Shibata Y, Hall H, Greenleaf AL, Strahl BD (2005) A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. Mol Cell Biol 25:3305–3316PubMedCrossRefGoogle Scholar
  61. 61.
    Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837PubMedCrossRefGoogle Scholar
  62. 62.
    Yuan W, Xie J, Long C, Erdjument-Bromage H, Ding X, Zheng Y, Tempst P, Chen S, Zhu B, Reinberg D (2009) Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo. J Biol Chem 284:15701–15707PubMedCrossRefGoogle Scholar
  63. 63.
    Li Y, Trojer P, Xu CF, Cheung P, Kuo A, Drury WJ 3rd, Qiao Q, Neubert TA, Xu RM, Gozani O et al (2009) The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 284:34283–34295PubMedCrossRefGoogle Scholar
  64. 64.
    Humpal SE, Robinson DA, Krebs JE (2009) Marks to stop the clock: histone modifications and checkpoint regulation in the DNA damage response. Biochem Cell Biol 87:243–253PubMedCrossRefGoogle Scholar
  65. 65.
    Tachibana M, Sugimoto K, Fukushima T, Shinkai Y (2001) Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem 276:25309–25317PubMedCrossRefGoogle Scholar
  66. 66.
    Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y (2002) A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296:1132–1136PubMedCrossRefGoogle Scholar
  67. 67.
    Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H et al (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16:1779–1791PubMedCrossRefGoogle Scholar
  68. 68.
    Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD (2003) Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 12:1591–1598PubMedCrossRefGoogle Scholar
  69. 69.
    Peters AH, Kubicek S, Mechtler K, O’Sullivan RJ, Derijck AA, Perez-Burgos L, Kohlmaier A, Opravil S, Tachibana M, Shinkai Y et al (2003) Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell 12:1577–1589PubMedCrossRefGoogle Scholar
  70. 70.
    Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y (2005) Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev 19:815–826PubMedCrossRefGoogle Scholar
  71. 71.
    Sampath SC, Marazzi I, Yap KL, Sampath SC, Krutchinsky AN, Mecklenbrauker I, Viale A, Rudensky E, Zhou MM, Chait BT et al (2007) Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol Cell 27:596–608PubMedCrossRefGoogle Scholar
  72. 72.
    Roopra A, Qazi R, Schoenike B, Daley TJ, Morrison JF (2004) Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes. Mol Cell 14:727–738PubMedCrossRefGoogle Scholar
  73. 73.
    Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Rao A, Shi Y (2007) The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 447:601–605PubMedCrossRefGoogle Scholar
  74. 74.
    Ding N, Zhou H, Esteve PO, Chin HG, Kim S, Xu X, Joseph SM, Friez MJ, Schwartz CE, Pradhan S et al (2008) Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation. Mol Cell 31:347–359PubMedCrossRefGoogle Scholar
  75. 75.
    Schwartz CE, Tarpey PS, Lubs HA, Verloes A, May MM, Risheg H, Friez MJ, Futreal PA, Edkins S, Teague J et al (2007) The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet 44:472–477PubMedCrossRefGoogle Scholar
  76. 76.
    Schaefer A, Sampath S, Intrator A, Min A, Gertler T, Surmeier DJ, Tarakhovsky A, Greengard P (2009) Control of cognition and adaptive behavior by the GLP/G9a epiegnetic suppressor complex. Neuron 64(5):678–691PubMedCrossRefGoogle Scholar
  77. 77.
    Cormier-Daire V, Molinari F, Rio M, Raoul O, de Blois MC, Romana S, Vekemans M, Munnich A, Colleaux L (2003) Cryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood? J Med Genet 40:300–303PubMedCrossRefGoogle Scholar
  78. 78.
    Goldstone AP, Beales PL (2008) Genetic obesity syndromes. Front Horm Res 36:37–60PubMedCrossRefGoogle Scholar
  79. 79.
    Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, McGill BE, Goulding EH, Sullivan E, Tecott LH et al (2008) Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59:947–958PubMedCrossRefGoogle Scholar
  80. 80.
    Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, Turner A et al (2009) Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 46(9):598–606PubMedCrossRefGoogle Scholar
  81. 81.
    Verhoeven WM, Kleefstra T, Egger JI (2010) Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients. Am J Med Genet B Neuropsychiatr Genet 153B(2):536–541PubMedGoogle Scholar
  82. 82.
    Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP et al (2006) Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 79:370–377PubMedCrossRefGoogle Scholar
  83. 83.
    Scheele S, Nystrom A, Durbeej M, Talts JF, Ekblom M, Ekblom P (2007) Laminin isoforms in development and disease. J Mol Med 85:825–836PubMedCrossRefGoogle Scholar
  84. 84.
    Benarafa C, Cooley J, Zeng W, Bird PI, Remold-O’Donnell E (2002) Characterization of four murine homologs of the human ov-serpin monocyte neutrophil elastase inhibitor MNEI (SERPINB1). J Biol Chem 277:42028–42033PubMedCrossRefGoogle Scholar
  85. 85.
    Oien KA, McGregor F, Butler S, Ferrier RK, Downie I, Bryce S, Burns S, Keith WN (2004) Gastrokine 1 is abundantly and specifically expressed in superficial gastric epithelium, down-regulated in gastric carcinoma, and shows high evolutionary conservation. J Pathol 203:789–797PubMedCrossRefGoogle Scholar
  86. 86.
    Niyonsaba F, Ushio H, Nagaoka I, Okumura K, Ogawa H (2005) The human beta-defensins (−1, −2, −3, −4) and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes. J Immunol 175:1776–1784PubMedGoogle Scholar
  87. 87.
    Bailey CM, Khalkhali-Ellis Z, Seftor EA, Hendrix MJ (2006) Biological functions of maspin. J Cell Physiol 209:617–624PubMedCrossRefGoogle Scholar
  88. 88.
    Holmes RS, Cox LA, Vandeberg JL (2008) Mammalian carboxylesterase 5: comparative biochemistry and genomics. Comp Biochem Physiol Part D Genomics Proteomics 3:195–204PubMedCrossRefGoogle Scholar
  89. 89.
    Jensen EV, Jacobson HI, Walf AA, Frye CA (2010) Estrogen action: a historic perspective on the implications of considering alternative approaches. Physiol Behav 99(2):151–162PubMedCrossRefGoogle Scholar
  90. 90.
    Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz CE, Lespinasse J, Van Esch H, Lacombe D, Goizet C et al (2005) Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet 42:780–786PubMedCrossRefGoogle Scholar
  91. 91.
    Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ (2009) PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N{varepsilon}-dimethyl lysine demethylase. Hum Mol Genet 19(2):217–222Google Scholar
  92. 92.
    Abidi FE, Miano MG, Murray JC, Schwartz CE (2007) A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin Genet 72:19–22PubMedCrossRefGoogle Scholar
  93. 93.
    Koivisto AM, Ala-Mello S, Lemmela S, Komu HA, Rautio J, Jarvela I (2007) Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin Genet 72:145–149PubMedCrossRefGoogle Scholar
  94. 94.
    Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y (2007) The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128:1077–1088PubMedCrossRefGoogle Scholar
  95. 95.
    Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, Janecke AR, Tariverdian G, Chelly J, Fryns JP et al (2005) Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am J Hum Genet 76:227–236PubMedCrossRefGoogle Scholar
  96. 96.
    Santos C, Rodriguez-Revenga L, Madrigal I, Badenas C, Pineda M, Mila M (2006) A novel mutation in JARID1C gene associated with mental retardation. Eur J Hum Genet 14:583–586PubMedCrossRefGoogle Scholar
  97. 97.
    Tzschach A, Lenzner S, Moser B, Reinhardt R, Chelly J, Fryns JP, Kleefstra T, Raynaud M, Turner G, Ropers HH et al (2006) Novel JARID1C/SMCX mutations in patients with X-linked mental retardation. Hum Mutat 27:389PubMedCrossRefGoogle Scholar
  98. 98.
    Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560PubMedCrossRefGoogle Scholar
  99. 99.
    Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227PubMedCrossRefGoogle Scholar
  100. 100.
    Rayasam GV, Wendling O, Angrand PO, Mark M, Niederreither K, Song L, Lerouge T, Hager GL, Chambon P, Losson R (2003) NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J 22:3153–3163PubMedCrossRefGoogle Scholar
  101. 101.
    Wang GG, Cai L, Pasillas MP, Kamps MP (2007) NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9:804–812PubMedCrossRefGoogle Scholar
  102. 102.
    Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y (2009) A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf–Hirschhorn syndrome. Nature 460:287–291PubMedCrossRefGoogle Scholar
  103. 103.
    Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y et al (2002) Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365–366PubMedCrossRefGoogle Scholar
  104. 104.
    Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S, Hughes HE, Cole TR, Rahman N (2003) NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet 72:132–143PubMedCrossRefGoogle Scholar
  105. 105.
    Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, Horn D, Hughes HE, Temple IK, Faravelli F et al (2005) Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet 77:193–204PubMedCrossRefGoogle Scholar
  106. 106.
    Bondy SC, Roberts S, Morelos BS (1970) Histone-acetylating enzyme of brain. Biochem J 119:665–672PubMedGoogle Scholar
  107. 107.
    Wolffe AP (1996) Histone deacetylase: a regulator of transcription. Science 272:371–372PubMedCrossRefGoogle Scholar
  108. 108.
    Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature 389:349–352PubMedCrossRefGoogle Scholar
  109. 109.
    Guan Z, Giustetto M, Lomvardas S, Kim JH, Miniaci MC, Schwartz JH, Thanos D, Kandel ER (2002) Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111:483–493PubMedCrossRefGoogle Scholar
  110. 110.
    Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559PubMedCrossRefGoogle Scholar
  111. 111.
    Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A (2004) Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42:947–959PubMedCrossRefGoogle Scholar
  112. 112.
    Yeh SH, Lin CH, Gean PW (2004) Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol Pharmacol 65:1286–1292PubMedCrossRefGoogle Scholar
  113. 113.
    Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB, Brindle PK, Abel T et al (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci 27:6128–6140PubMedCrossRefGoogle Scholar
  114. 114.
    Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ et al (1995) Rubinstein–Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376:348–351PubMedCrossRefGoogle Scholar
  115. 115.
    Kalkhoven E, Roelfsema JH, Teunissen H, den Boer A, Ariyurek Y, Zantema A, Breuning MH, Hennekam RC, Peters DJ (2003) Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein–Taybi syndrome. Hum Mol Genet 12:441–450PubMedCrossRefGoogle Scholar
  116. 116.
    Coupry I, Monnet L, Attia AA, Taine L, Lacombe D, Arveiler B (2004) Analysis of CBP (CREBBP) gene deletions in Rubinstein–Taybi syndrome patients using real-time quantitative PCR. Hum Mutat 23:278–284PubMedCrossRefGoogle Scholar
  117. 117.
    Coupry I, Roudaut C, Stef M, Delrue MA, Marche M, Burgelin I, Taine L, Cruaud C, Lacombe D, Arveiler B (2002) Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. J Med Genet 39:415–421PubMedCrossRefGoogle Scholar
  118. 118.
    Roelfsema JH, White SJ, Ariyurek Y, Bartholdi D, Niedrist D, Papadia F, Bacino CA, den Dunnen JT, van Ommen GJ, Breuning MH et al (2005) Genetic heterogeneity in Rubinstein–Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet 76:572–580PubMedCrossRefGoogle Scholar
  119. 119.
    Hennekam RC (2006) Rubinstein–Taybi syndrome. Eur J Hum Genet 14:981–985PubMedCrossRefGoogle Scholar
  120. 120.
    Murata T, Kurokawa R, Krones A, Tatsumi K, Ishii M, Taki T, Masuno M, Ohashi H, Yanagisawa M, Rosenfeld MG et al (2001) Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein–Taybi syndrome. Hum Mol Genet 10:1071–1076PubMedCrossRefGoogle Scholar
  121. 121.
    Tanaka Y, Naruse I, Maekawa T, Masuya H, Shiroishi T, Ishii S (1997) Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein–Taybi syndrome. Proc Natl Acad Sci USA 94:10215–10220PubMedCrossRefGoogle Scholar
  122. 122.
    Yao TP, Oh SP, Fuchs M, Zhou ND, Ch’ng LE, Newsome D, Bronson RT, Li E, Livingston DM, Eckner R (1998) Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93:361–372PubMedCrossRefGoogle Scholar
  123. 123.
    Oike Y, Hata A, Mamiya T, Kaname T, Noda Y, Suzuki M, Yasue H, Nabeshima T, Araki K, Yamamura K (1999) Truncated CBP protein leads to classical Rubinstein–Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum Mol Genet 8:387–396PubMedCrossRefGoogle Scholar
  124. 124.
    Kung AL, Rebel VI, Bronson RT, Ch’ng LE, Sieff CA, Livingston DM, Yao TP (2000) Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev 14:272–277PubMedGoogle Scholar
  125. 125.
    Zhang Z, Hofmann C, Casanova E, Schutz G, Lutz B (2004) Generation of a conditional allele of the CBP gene in mouse. Genesis 40:82–89PubMedCrossRefGoogle Scholar
  126. 126.
    Wood MA, Kaplan MP, Park A, Blanchard EJ, Oliveira AM, Lombardi TL, Abel T (2005) Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem 12:111–119PubMedCrossRefGoogle Scholar
  127. 127.
    Wood MA, Attner MA, Oliveira AM, Brindle PK, Abel T (2006) A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes. Learn Mem 13:609–617PubMedCrossRefGoogle Scholar
  128. 128.
    Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–972PubMedCrossRefGoogle Scholar
  129. 129.
    Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60PubMedCrossRefGoogle Scholar
  130. 130.
    Lee J, Hagerty S, Cormier KA, Kim J, Kung AL, Ferrante RJ, Ryu H (2008) Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation. Hum Mol Genet 17:1774–1782PubMedCrossRefGoogle Scholar
  131. 131.
    Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 3rd (2002) SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 16:919–932PubMedCrossRefGoogle Scholar
  132. 132.
    Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (2002) Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21:148–152PubMedCrossRefGoogle Scholar
  133. 133.
    Wang H, An W, Cao R, Xia L, Erdjument-Bromage H, Chatton B, Tempst P, Roeder RG, Zhang Y (2003) mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol Cell 12:475–487PubMedCrossRefGoogle Scholar
  134. 134.
    Fischle W, Tseng BS, Dormann HL, Ueberheide BM, Garcia BA, Shabanowitz J, Hunt DF, Funabiki H, Allis CD (2005) Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438:1116–1122PubMedCrossRefGoogle Scholar
  135. 135.
    Johansen KM, Johansen J (2006) Regulation of chromatin structure by histone H3S10 phosphorylation. Chromosome Res 14:393–404PubMedCrossRefGoogle Scholar
  136. 136.
    Zippo A, De Robertis A, Serafini R, Oliviero S (2007) PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation. Nat Cell Biol 9:932–944PubMedCrossRefGoogle Scholar
  137. 137.
    Ivaldi MS, Karam CS, Corces VG (2007) Phosphorylation of histone H3 at Ser10 facilitates RNA polymerase II release from promoter-proximal pausing in Drosophila. Genes Dev 21:2818–2831PubMedCrossRefGoogle Scholar
  138. 138.
    Kagan A, McDonald TV (2005) Dynamic control of hERG/I(Kr) by PKA-mediated interactions with 14-3-3. Novartis Found Symp 266:75–89, discussion 89-99PubMedCrossRefGoogle Scholar
  139. 139.
    Mateescu B, England P, Halgand F, Yaniv M, Muchardt C (2004) Tethering of HP1 proteins to chromatin is relieved by phosphoacetylation of histone H3. EMBO Rep 5:490–496PubMedCrossRefGoogle Scholar
  140. 140.
    Hirota T, Lipp JJ, Toh BH, Peters JM (2005) Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438:1176–1180PubMedCrossRefGoogle Scholar
  141. 141.
    Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S, Hanauer A, Allis CD (1999) Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285:886–891PubMedCrossRefGoogle Scholar
  142. 142.
    Soloaga A, Thomson S, Wiggin GR, Rampersaud N, Dyson MH, Hazzalin CA, Mahadevan LC, Arthur JS (2003) MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J 22:2788–2797PubMedCrossRefGoogle Scholar
  143. 143.
    Chwang WB, O’Riordan KJ, Levenson JM, Sweatt JD (2006) ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn Mem 13:322–328PubMedCrossRefGoogle Scholar
  144. 144.
    Hanauer A, Young ID (2002) Coffin-Lowry syndrome: clinical and molecular features. J Med Genet 39:705–713PubMedCrossRefGoogle Scholar
  145. 145.
    Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I, Mandel JL, Sassone-Corsi P, Hanauer A (1996) Mutations in the kinase Rsk-2 associated with Coffin–Lowry syndrome. Nature 384:567–570PubMedCrossRefGoogle Scholar
  146. 146.
    Yntema HG, van den Helm B, Kissing J, van Duijnhoven G, Poppelaars F, Chelly J, Moraine C, Fryns JP, Hamel BC, Heilbronner H et al (1999) A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Genomics 62:332–343PubMedCrossRefGoogle Scholar
  147. 147.
    Dufresne SD, Bjorbaek C, El-Haschimi K, Zhao Y, Aschenbach WG, Moller DE, Goodyear LJ (2001) Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice. Mol Cell Biol 21:81–87PubMedCrossRefGoogle Scholar
  148. 148.
    Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM et al (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin–Lowry Syndrome. Cell 117:387–398PubMedCrossRefGoogle Scholar
  149. 149.
    Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273:959–963PubMedCrossRefGoogle Scholar
  150. 150.
    De Cesare D, Jacquot S, Hanauer A, Sassone-Corsi P (1998) Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci USA 95:12202–12207PubMedCrossRefGoogle Scholar
  151. 151.
    Merienne K, Pannetier S, Harel-Bellan A, Sassone-Corsi P (2001) Mitogen-regulated RSK2-CBP interaction controls their kinase and acetylase activities. Mol Cell Biol 21:7089–7096PubMedCrossRefGoogle Scholar
  152. 152.
    Brami-Cherrier K, Valjent E, Herve D, Darragh J, Corvol JC, Pages C, Arthur SJ, Girault JA, Caboche J (2005) Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J Neurosci 25:11444–11454PubMedCrossRefGoogle Scholar
  153. 153.
    Stipanovich A, Valjent E, Matamales M, Nishi A, Ahn JH, Maroteaux M, Bertran-Gonzalez J, Brami-Cherrier K, Enslen H, Corbille AG et al (2008) A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453:879–884PubMedCrossRefGoogle Scholar
  154. 154.
    Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21PubMedCrossRefGoogle Scholar
  155. 155.
    Prendergast GC, Ziff EB (1991) Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science 251:186–189PubMedCrossRefGoogle Scholar
  156. 156.
    Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286:481–486PubMedCrossRefGoogle Scholar
  157. 157.
    Jorgensen HF, Bird A (2002) MeCP2 and other methyl-CpG binding proteins. Ment Retard Dev Disabil Res Rev 8:87–93PubMedCrossRefGoogle Scholar
  158. 158.
    Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278:4035–4040PubMedCrossRefGoogle Scholar
  159. 159.
    Miranda TB, Jones PA (2007) DNA methylation: the nuts and bolts of repression. J Cell Physiol 213:384–390PubMedCrossRefGoogle Scholar
  160. 160.
    Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 133:1145–1148PubMedCrossRefGoogle Scholar
  161. 161.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935PubMedCrossRefGoogle Scholar
  162. 162.
    Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–930PubMedCrossRefGoogle Scholar
  163. 163.
    Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869PubMedCrossRefGoogle Scholar
  164. 164.
    Miller CA, Campbell SL, Sweatt JD (2008) DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol Learn Mem 89:599–603PubMedCrossRefGoogle Scholar
  165. 165.
    Chahrour M, Zoghbi HY (2007) The story of Rett syndrome: from clinic to neurobiology. Neuron 56:422–437PubMedCrossRefGoogle Scholar
  166. 166.
    Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257PubMedCrossRefGoogle Scholar
  167. 167.
    Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 96:14412–14417PubMedCrossRefGoogle Scholar
  168. 168.
    Gimelli G, Varone P, Pezzolo A, Lerone M, Pistoia V (1993) ICF syndrome with variable expression in sibs. J Med Genet 30:429–432PubMedCrossRefGoogle Scholar
  169. 169.
    Hagleitner MM, Lankester A, Maraschio P, Hulten M, Fryns JP, Schuetz C, Gimelli G, Davies EG, Gennery A, Belohradsky BH et al (2008) Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet 45:93–99PubMedCrossRefGoogle Scholar
  170. 170.
    Ehrlich M, Sanchez C, Shao C, Nishiyama R, Kehrl J, Kuick R, Kubota T, Hanash SM (2008) ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation. Autoimmunity 41:253–271PubMedCrossRefGoogle Scholar
  171. 171.
    Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J et al (2008) DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 17:690–709PubMedCrossRefGoogle Scholar
  172. 172.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedCrossRefGoogle Scholar
  173. 173.
    Nan X, Campoy FJ, Bird A (1997) MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88:471–481PubMedCrossRefGoogle Scholar
  174. 174.
    Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191PubMedCrossRefGoogle Scholar
  175. 175.
    Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389PubMedCrossRefGoogle Scholar
  176. 176.
    Kaludov NK, Wolffe AP (2000) MeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. Nucleic Acids Res 28:1921–1928PubMedCrossRefGoogle Scholar
  177. 177.
    Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmenares C, Ishii S (2001) The Ski protein family is required for MeCP2-mediated transcriptional repression. J Biol Chem 276:34115–34121PubMedCrossRefGoogle Scholar
  178. 178.
    Kimura H, Shiota K (2003) Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1. J Biol Chem 278:4806–4812PubMedCrossRefGoogle Scholar
  179. 179.
    Harikrishnan KN, Chow MZ, Baker EK, Pal S, Bassal S, Brasacchio D, Wang L, Craig JM, Jones PL, Sif S et al (2005) Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing. Nat Genet 37:254–264PubMedCrossRefGoogle Scholar
  180. 180.
    Nan X, Hou J, Maclean A, Nasir J, Lafuente MJ, Shu X, Kriaucionis S, Bird A (2007) Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc Natl Acad Sci USA 104:2709–2714PubMedCrossRefGoogle Scholar
  181. 181.
    Gibbons RJ, Picketts DJ, Villard L, Higgs DR (1995) Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell 80:837–845PubMedCrossRefGoogle Scholar
  182. 182.
    Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J et al (2005) Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 77:442–453PubMedCrossRefGoogle Scholar
  183. 183.
    Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331PubMedCrossRefGoogle Scholar
  184. 184.
    Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326PubMedCrossRefGoogle Scholar
  185. 185.
    Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi H (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:243–254PubMedCrossRefGoogle Scholar
  186. 186.
    Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, David Sweatt J, Zoghbi HY (2004) Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet 13:2679–2689PubMedCrossRefGoogle Scholar
  187. 187.
    Gemelli T, Berton O, Nelson ED, Perrotti LI, Jaenisch R, Monteggia LM (2006) Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol Psychiatry 59:468–476PubMedCrossRefGoogle Scholar
  188. 188.
    Luikenhuis S, Giacometti E, Beard CF, Jaenisch R (2004) Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci USA 101:6033–6038PubMedCrossRefGoogle Scholar
  189. 189.
    Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–1147PubMedCrossRefGoogle Scholar
  190. 190.
    Giacometti E, Luikenhuis S, Beard C, Jaenisch R (2007) Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc Natl Acad Sci USA 104:1931–1936PubMedCrossRefGoogle Scholar
  191. 191.
    Heiman M, Schaefer A, Gong S, Peterson JD, Day M, Ramsey KE, Suarez-Farinas M, Schwarz C, Stephan DA, Surmeier DJ et al (2008) A translational profiling approach for the molecular characterization of CNS cell types. Cell 135:738–748PubMedCrossRefGoogle Scholar
  192. 192.
    Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, Ma G, Bupp S, Shrestha P, Shah RD, Doughty ML et al (2008) Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:749–762PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Anne Schaefer
    • 1
  • Alexander Tarakhovsky
    • 2
  • Paul Greengard
    • 1
  1. 1.Laboratory of Molecular and Cellular NeuroscienceThe Rockefeller UniversityNew YorkUSA
  2. 2.Laboratory of Lymphocyte SignalingThe Rockefeller UniversityNew YorkUSA

Personalised recommendations